1-(di-lower alkyl amino lower alkyl)-2-phenyl-5,6,7,8-tetrahydroindolizines

ABSTRACT

The tangible embodiments of this invention are the 1-(di-lower alkyl amino lower alkyl)-2-phenyl-5,6,7,8-tetrahydroindolizines and the non-toxic acid addition and quaternary salts thereof, which are of pharmacological importance in that they exert an influence on the central nervous system of animals. They vary in activity from depressants to stimulants depending upon the specific compound being used, the dose administered and the animal species to which it is administered. These compounds may be administered orally as the free base or in the form of a nontoxic acid addition or quaternary salt.

United States Patent [191 Walter [541 l-(Dl-LOWER ALKYL AMINO LOWER ALKYL)-2-PHENYL-5,6,7,8- TETRAHYDROINDOLIZINES [76] Inventor: Lewis A. Walter, 167 Central Ave.,

Madison, NJ. 07940 [22] Filed: June 1, 1970 [21] Appl. No.: 42,593

Related US. Application Data [60] Division of Ser. No. 854,015, Aug. ll, 1969, which is a continuation of Ser. No. 57l,426, Aug. 10, I966, abandoned.

[52] US. Cl. .260/293.53, 260/247.5 B, 260/268 BC,

260/296 H, 424/248, 424/250, 424/267 [51] Int. Cl. ..C07d 39/00 [58] Field of Search ..260/293.53, 293.55, 296 H [5 6] References Cited OTHER PUBLICATIONS Barrett et al., J. Chem. Soc. 1958, 338-339.

[451 Feb. 20, 1973 Primary Examiner-Henry B. Jiles Assistant ExaminerG. Thomas Todd Anorney-Carver C. Joyner, Stephen B. Coan and Raymond A. McDonald 5 7 ABSTRACT The tangible embodiments of this invention are the 1- (di-lower alkyl amino lower alkyl)-2-phenyl-5,6,7,8- tetrahydroindolizines and the non-toxic acid addition and quaternary salts thereof, which are of pharmacological importance in that they exert an influence on the central nervous system of animals. They vary in activity from depressants to stimulants depending upon the specific compound being used, the dose administered and the animal species to which it is administered. These compounds may be administered orally as the free base or in the form of a non-toxic acid addition or quaternary salt.

4 Claims, No Drawings l-(DI-LOWER ALKYL AMINO LOWER ALKYL)-2- PHENYL-S ,6,7 ,8-TETRAHYDROINDOLIZINES Z-phenylindolizines. More particularly, this invention relates to l-tertiary amino lower alkyl-2-phenylindolizines, pharmaceutically acceptable quaternary salts thereof and to methods of making such compositions.

The invention sought to be patented in one of its composition aspects is described as residing in the concept of a chemical compound having the molecular structure of a Z-phenyl-indolizine (and the 5,6,7,8 tetrahydro analog thereof) to which there is attached at the l-position a tertiary amino lower alkyl group.

The invention sought to be patented in another of its composition aspects is described as residing in the concept of a pharmaceutically acceptable quaternary salt of the aforementioned tangible embodiment.

The invention sought to be patented in its process aspects is described as residing in the concept of preparing quaternary salts of the free base tangible embodiment described hereinabove by reaction of said free base with a quaternizing agent so as to produce a pharm aceutically acceptable quaternary salt.

The quaternary salts of this invention possess the applied use characteristic of exerting an anti-microbial action as demonstrated by in vitro tests on representative bacteria, yeast and fungi when cultivated on agar plates. The salts are also anthelmintic in character by virtue of their action against pinworms. The preferred use of the tertiary amines is as intermediates in the preparation of the quaternary salts.

The tangible embodiments of this invention may be represented as members of the group consisting of ter tiary amines having the following formula:

and the pharmaceutically acceptable quaternary salts thereof, wherein X represents hydrogen, halogen, lower alkyl or lower alkoxy; R and R represent lower alkyl or together with the nitrogen to which they are attached represent a nitrogen heterocycle having 5-6 cyclic members and Z represents an alkylene bridge being either straight or branched chain having one to four carbon atoms and the dotted linesrepresent optional double bonds.

As used herein, the term lower alkyl means saturated hydrocarbon radicals of up to and including six carbon atoms, and, include both straight and branched chain groups. Representative of such groups are methyl, ethyl, propyl, butyl, pentyl and hexyl and their branched chain isomers. The term lower alkoxy means a lower alkyl group attached to an ether oxygen and is similarly limited to six carbon atoms.

When R, and R, together with the nitrogen atom to which they are attached form a nitrogen heterocycle having five to six cyclic atoms, the group so formed is represented by pyrrolidino, piperidino, morpholino and piperazino which themselves may contain additional alkyl or hydroxy alkyl substituents.

The term pharmaceutically acceptable quaternary salts as used herein designates the reaction product of the tertiary amine tangible embodiment with a lower alkyl or phenyl lower alkyl ester of an inorganic acid. Exemplary of such acids are hydrohalic (preferably chloride, bromide oriodide), sulfuric and the like. Representative of such salts are those formed by reacting the tertiary amine embodiment with, for example, a lower alkyl halide such as methyl iodide, ethyl bromide, butyl chloride; or with benzyl chloride or phenethyl bromide; or with dimethylsulfate or diethylsulfate. Other anions may be introduced directly by quaternizing in the usual manner or indirectly, in a known manner such as, by reacting a quaternary chloride with silver nitrate or phosphate or acetate whereby anion exchange occurs with the insoluble silver chloride precipitating.

The tertiary amines of this invention are preferably prepared by the reaction of a 2-pyridyl-lower alkanoyl amide, bearing R and R substituents on the amido nitrogen, with an a-bromoacetophenone to yield a phenacyl pyridinium bromide. Exemplary of the foregoing, N,N-dimethyl-3(Z-pyridyl) propionamide (II) with an a-bromoacetophenone yields the phenacyl pyridinium bromide (Ill). The a-bromoacetophenone reagent optionally may bear the substituent X on the benzene ring, X being as heretofore defined. The formation of the phenacyl pyridinium halide (III) is effected in a known manner usually by admixing the reactants and heating until reaction is initiated after which time an exothermic reaction occurs. Upon treatment with mild aqueous base, such as saturated sodium bicarbonate solution or aqueous alkali, compound Ill undergoes intramolecular condensation forming the amide, IV. Reduction of the amide, with lithium alu-. minum hydride, for example, results in the formation of the tertiary amino embodiment of formula I.-This sequence of reactions depicted by the following scheme: CHzBr (cameo NR Rz (CH2)2C oNRiRz l Base CHzC ONRrRs atoms, and R, and R, are methyl, however, these are variable dependent upon choice of starting material.

Br III Reaction of the tertiary amine produced, with a quater nizing agent, either with or without solvent, as described herein, yields the appropriate pharmaceutically acceptable quaternary salt.

Alternatively, the tertiary amines of this invention are preparable by reacting a Z-pyridyl lower alkyl primary amine with a chlorocarbonic ester giving rise to an N-carbalkoxy-(2-pyridyl)-lower alkyl amine, which upon reaction with an a-bromoacetophenone followed by treatment with base and then reduction as described above, results in the formation of a compound having formula 1 except that R is hydrogen. N-alkylation is effected in the usual manner, such as, by reaction of the secondary amine with an alkyl halide obtaining a tertiary amine of this invention.

The tertiary amines obtained by the foregoing reactions may be converted to their 5,6,7,8 tetrahydro analogs by catalytic hydrogenation in the presence of Raney Nickel at from to 60 p.s.i.g. in a suitable solvent, such. as, an alkanol for example.

As indicated, the tertiary amines may be reacted with quarternizing agents by admixture in a suitable solvent and allowing the reaction to proceed at a convenient temperature for from a few hours up to several days followed by collection of the insoluble product by filtration. By suitable solvent is meant one in which the reactants are soluble but the quaternary salt is not (such as ethyl ether or tetrahydrofuran). Polar solvents can be used, such as alkanols, however, the quaternary salts may be soluble in such solvents and may be recoverable therefrom by concentration and crystallization or by addition of a miscible non-polar solvent as a precipitant.

The quaternary salts of this invention are broad spectrum antimicrobial agents exhibiting a potent antimicrobial action against such organisms as Staphylococcus aureus, Streptococcus pyogenes c., Eschericia coli, Salmonella schottmuelleri, Candida Albicans and Trichophyron menragrophytes in standard in vitro tests. The quaternaries, additionally, are effective against the mouse pinworm, Syphacia obvelata, and are therefore, suited for the disinfection of cages, laboratory equipment, floors and tables. In disinfecting cages, the quaternary salts may be applied to the mature pinworm, or applied to their larvae; both forms being excreted in the droppings of infected animals. These compounds provide both a useful substitute and adjunct to present disinfection practice. These tangible embodiments, being quaternary salts, may be used as aqueous solutions or suspensions in concentrations up to 10 percent (weight to volume) in combination with soaps and detergents or utilized alone as a final lavage in areas being disinfected.

The tertiary amine tangible embodiments are of pharmacological importance in addition to being useful intermediates. They exert a valuable influence on the central nervous systems of animals, varying from depressants to stimulants depending on the embodiment under test, the dose administered and the animal species used. These amines may be administered orally in the free base form or in the form of a non-toxic acid addition salt (such as hydrochloride, maleate, sulfate and the like).

EXAMPLE 1 l-[ 2-( N-Methylmorpholinium )ethyl]-2-Phenylindolizine Bromide A. Dissolve 20 g. of ethyl 3-(2-pyridyl)-propionate in 50 g. of morpholine and add 1 g. of sodium methylate. Reflux the solution for 8 hours and distill the excess morpholine in vacuo. Dissolve the residue in ether, wash with water, dry over anhydrous potassium carbonate, filter and distill the filtrate to give 3-( 2-pyridyl) propionyl morpholide, B.P. l50-l 60 at 1 mm.

B. Mix 5 g. of the product from A with 4.5 g. of abromo-acetop'henone and warm slowly to C whereupon a vigorous reaction is initiated. Remove the heat source until the reaction moderates, continue the heating for 2 hours on a steam bath. Cool the mixture and shake it with ml. of ether and with 100 ml. of water. Separate the layers and heat the aqueous solution on a steam bath with 50 ml. of saturated sodium bicarbonate for 40 minutes. The greenish-brown phenylindolizine compound separates out upon cooling. Ex-

tract the product with ether and dry the ethereal solution over anhydrous potassium carbonate. Filter the solution and add it slowly to a stirred refluxing mixture of 5 g. of lithium aluminum hydride in 500 ml. of ether under a nitrogen atmosphere. Continue refluxing the mixture for 5 hours after the addition is complete. Cool the reaction mixture, add 4.5 ml. of water dropwise followed by 4.5 ml. of 15 percent sodium hydroxide and finally another 14 ml. of water. Allow the reaction mixture to stand for 1 hour then filter to remove the precipitated inorganic salts. Wash the salt cake with ether and dry the ether filtrate and washes over anhydrous potassium carbonate. Filter the dried solution and saturate it with methyl bromide. Close the container and keep it in the dark at room temperature for 2 days. Collect the precipitate consisting of the l-[2-(N- Methylmorpholinium)-ethyl]-2-phenylindolizine bromide by filtration and dry in vacuo.

EXAMPLE 2 EXAMPLE 3 l-[ 3-(N ,N -Dimethylamino )-propyl] -2-Phenylindolizine A. Dissolve 7.5 g. of N,N-dimethyl-4-(2-pyridyl)-butyramide in 250 ml. of dry benzene at reflux. Add 10 g. of 2-bromoacetophenone and continue refluxing for 24 hours. Filter the precipitated quaternary salt and wash with dry benzene. Dissolve the precipitate in a mixture of l50 ml. of water and l00 ml. of ether. Separate the layers, add to the aqueous later 100 ml. of saturated sodium bicarbonate solution and heat the mixture on a steam bath for 45 minutes. Extract the precipitate of l- (3-N,N dimethylpropionamino)-2 phenylindolizine with 100 ml. of ether. Dry the ethereal extract over anhydrous potassium carbonate and concentrate to obtain crystalline l-(3-N,N-dimethyl propionamido)-2- phenylindolizine m.p. 9395.

B. Dissolve 7.5 g. of the crystalline amide in 70 ml. of dry ether and add this solution dropwise to a stirred, refluxing suspension of 3.5 g. of lithium aluminum hydride in 500 ml. of ether. Continue refluxing and stirring the reaction for 6 hours. Cool the reaction mixture and treat consecutively with 3 ml. of water, 3 ml. of 15 percent sodium hydroxide and ml. of water. Filter the precipitated salts, after having allowed the mixture to stir for 1 hour. Wash the inorganic precipitate with ether. Combine the filtrate and the washes and dry over anhydrous potassium carbonate. Filter and concentrate the filtrate to a residue under an inert atmosphere. The 1-(3-N,-N-dimethylaminopropyl)-2-phenylindolizine is obtained as a light yellow oil weighing 7 g.

EXAMPLE 4 1-[3-(Trimethylammonium )-propyl]-2-phenylindolizine Bromide Dissolve 5.0 gms. of the product of Example 3 in 500 ml. of dry ether and saturate with methyl bromide. Close the container and keep it in the dark at room temperature for 2 days. Collect the 1-(3-trimethylammoniumpropyl)-2-phenylindolizine bromide by filtration and wash the solids free of entrapped filtrate with fresh anhydrous ethyl ether. Dry in vacuo to obtain the product of this example.

EXAMPLE 5 1-[2-(N,N-Dimethylamino)-ethyl]-2-Phenylindolizine A. 3-( 2-Pyridyl)-Propylamine Saturate a solution of 52 g. of 3-(2-pyridyl)- propionitrile in 400 ml. of ethanol with ammonia. Hydrogenate at 70-75 in the presence of 10 gms. of Raney Nickel catalyst and under 500 p.s.i. Filter the suspension and concentrate the filtrate to a residue. Distil the residue in vacuo, b.p. l141 17 (4 mm) to obtain 3-(2-pyridyl)-propylamine (n,, 1.5135).

B. N-carbethoxy-3-( 2-pyridyl)-propylamine Dissolve 34 g. of the amine prepared in (A) and 5 g. of pyridine in 150 ml. of chloroform with stirring and cool to below 40. Add 33 g. of ethyl chlorocarbonate, allow the reaction to proceed for several hours, add 25 ml. of water and stir for 2 hours. Add a solution of sodium hydroxide with cooling and stirring and continue the addition until the reaction mixture is very alkaline.

Separate the chloroform layer and after drying over anhydrous sodium carbonate remove the solvent by distillation. Distil the residue to obtain 46 g. N-carbethoxy- 3-(2-pyridyl)-propylamine, b.p. 137-l40C (3 mm) n 1.5091.

C. N-Methyl-3-(2-pyridyl)-Propylamine Add dropwise 27.5 g. of the carbethoxy compound from step (B) to a stirring and refluxing suspension of 10 g. of lithium aluminum hydride in 500 ml. of ether. Continue the reaction for 6 hours; cool the mixture and treat consecutively with 9 ml. of water, 9 ml. of percent sodium hydroxide and 27 ml. of water. Stir the reaction mixture for 1 hour, filter the resulting suspension of inorganic salts and wash with ether. Combine the ether filtrate and washes; evaporate to a residue and distill the residue in vacuo to yield 18 g. of N- methyl-3-(2-pyridyl)-propylamine, b.p. 6569C (2 mm) n 1.4983.

D. N-Methyl-N-carbethoxy-3-( 2-pyridyl)- Propylamine Treat the compound from step (C) with ethyl chlorocarbonate as described in step (B) and form the compound of this example, b.p. 132-134 (3 mm) m, 1.4983.

E. l-[2-(N,N-Dimethylamino)-ethyl]-2-Pheny1in' dolizine Reflux 18 g. of the product of step (D) with 20 g. of a-bromoacetophenone in 500 ml. of dry benzene for 24 hours. Separate the precipitated quaternary salt by decanting the solvent. Dissolve the salt in a mixture of 150 ml. of water and 100 ml. of ether and separate the layers. Heat the aqueous layer on a steam bath with 100 ml. of saturate sodium bicarbonate solution for minutes. Extract the precipitated I-(Z-N-methyl-N-carbethoxyaminoethyl)-2-phenylindolizine with ether, dry over anhydrous potassium carbonate, filter and reduce with lithium aluminum hydride, as in step (C), to yield 1- 2-( N ,N -dimethylamino )-ethyl -2 -phenylindolizine.

EXAMPLE 6 1-[2-N ,N-Dimethylamino)-ethyl]-2-phenyl-5 ,6,7 ,8- Tetrahydroindolizine Dissolve 8 g. of l-[2-(N,N-dimethylamino)-ethyl]-2- phenyl-indolizine in 160 ml. of alcohol and hydrogenate at 60 p.s.i. using 5 g. Raney Nickel as the catalyst. Filter the suspension discard the catalyst and remove the alcohol in vacuo. The 1-[2-(N,N- dimethylamino)'ethyl]-2-phenyl-5,6,7,8-tetrahydro4ndolizine remains as a yellow brown oil with a blue fluorescence which conversion to a. mono hydrochloride in a known manner yields a product melting 21 12l4C.

' EXAMPLE 7 1 2-(Trimethylammonium )-ethy1I-Z-phenylindolizine methosulfate Dissolve 10 gms. of 1-(2-N,N-dimethylaminoethyl)-2 -phenylindolizine, the product of Example 5 in 1,000 ml. of ethyl ether and treat with dimethyl sulfate for 2 days at room temperature. Collect the 1[2- (trimethylammonium )-ethyll-2-phenylindolizine methosulfate precipitate by filtration from the reaction mixture.

EXAMPLE 8 l-[ 3-(N-Benzyl-N,N-dimethylammonium )-propyl]-2- phenylindolizine Chloride Add 5 grams of the product of Example 3A in 150 ml. of dry ether slowly to a stirred refluxing mixture of 2 g. lithium aluminum hydride in 200 ml. of ethyl ether. Blanket the mixture with nitrogen and maintain at reflux for 5 hours. Cool the reaction mixture and add 2 ml. of water dropwise, followed by 2 ml. of 15 percent sodium hydroxide and subsequently by 6.0 ml. of water. Allow the reaction mixture to stand for 1 hour and filter. Wash the inorganic salts with ether and combine the filtrate and washes. Dry the ethereal layer over anhydrous potassium carbonate. Filter the dried solution and concentrate to a residue. Dissolve the residue in ml. of dry benzene and add 4.0 gms. of benzyl chloride. Blanket the reaction mixture with nitrogen and warm to 50C. The quaternary salt separates as an oil which crystallizes on standing Isolate the product of this example by filtration, wash with benzene and vacuum dry.

EXAMPLE 9 1-[3-(N-Benzyl-N,N-dimethylammonium)-propyl]-2- phenylindolizine Nitrate Dissolve 1.0 g. of the product of Example 8 in 10 ml. of distilled water and add 5.0 ml. of a solution containing 0.45 g. silver nitrate with stirring. Age the reaction mixture until the silver chloride precipitate coalesces, filter using a filter aid and evaporate the filtrate to a residue in vacuo to yield the title product.

EXAMPLE l vention is particularly pointed out and distinctly claimed as follows:

1. A compound selected from the group consisting of a phenylindolizine having the following structural formula:

and the N-lower alkyl and N-phenyl lower alkyl quaternary salts thereof, wherein R and R are each lower alkyl; and Z is an alkylene bridge having one to four carbon atoms.

2. A compound of claim 1 wherein Z is ethylene, R

. and R2 are methyl, said compound being l-[2-(N,N-'

dimethylamino )-ethyl ]-2-phenyl-5 ,6,7 ,S-tetrahydroindolizine.

3. A methyl bromide quaternary salt of a compound of claim 2 wherein Z is ethylene, R and R are methyl, said compound being l-[2-(trimethylammonium)- ethyl ]-2-phenyl-5 ,6,7,S-tetrahydroindolizine bromide.

4. A methyl bromide quaternary salt of a compound of claim 1 wherein Z is propylene, R and R are methyl, said compound being l-[3-(trimethylammoniurn )-propyl]-2-phenyl-5,6,7 ,S-tetrahydroindolizine. 

1. A compound selected from the group consisting of a phenylindolizine having the following structural formula:
 2. A compound of claim 1 wherein Z is ethylene, R1 and R2 are methyl, said compound being 1-(2-(N,N-dimethylamino)-ethyl)-2-phenyl-5,6,7,8-tetrahydroindolizine.
 3. A methyl bromide quaternary salt of a compound of claim 2 wherein Z is ethylene, R1 and R2 are methyl, said compound being 1-(2-(trimethylammonium)-ethyl)-2-phenyl-5,6,7,8-tetrahydroindolizine bromide.
 4. A methyl bromide quaternary salt of a compound of claim 1 wherein Z is propylene, R1 and R2 are methyl, said compound being 1-(3-(trimethylammonium)-propyl)-2-phenyl-5,6,7,8-tetrahydroindolizine. 